重复使用阿片类药物并不总是能缓解基础疼痛,程序性疼痛,或烧伤后两者兼而有之。减轻烧伤部位疼痛可以通过GTS-21刺激α7-乙酰胆碱烟碱受体(α7AChRs)和减少大鼠小胶质细胞激活来实现。我们检验了以下假设:吗啡夸大了烧伤部位的疼痛,而GTS-21减轻了吗啡引起的加重的烧伤损伤疼痛和小胶质细胞激活。
幼鼠有足背烧伤或假烧伤,接受腹腔生理盐水,吗啡,GTS-21或组合,每天两次,共14天。从第0-20天的早晨药物之前每隔一天测试同侧足底疼痛阈值。脊髓小胶质细胞激活,证明为疼痛传感器(肿瘤坏死因子-α[TNF-α],白细胞介素[IL]-6,IL-1β,核因子κB[NF-κB],Toll样受体4[TLR4])表达,使用免疫组织化学和免疫印迹检查。在培养的小胶质细胞中,检测吗啡诱导的细胞因子表达(定量聚合酶链反应/酶联免疫吸附测定[qPCR/ELISA])。
吗啡在假烧伤第5天加重了异常性疼痛(P=0.039,n=8-11),但在第3天明显加重了烧伤部位异常性疼痛(P=0.010,n=8-11)。小胶质细胞增生与伤害性行为变化平行,其中吗啡烧伤与烧伤相比,小胶质细胞增生最高。单独使用吗啡,或对照(每个字段的细胞数[SD]:33.8[2.4],18.0[4.1],8.2[1.9],和4.8[2.0],分别为;P<0.001,n=4-5]。GTS-21逆转了假烧伤和烧伤大鼠中吗啡诱导的疼痛成分,同时减少了小胶质细胞增生和脊髓疼痛传感器的表达(TNF-α,IL-6,IL-1β,NF-κB,和TLR4)。暴露于吗啡的小胶质细胞显示细胞因子表达增加,GTS-21缓解了这种情况。
单独使用吗啡或烧伤会增加疼痛,并伴有小胶质细胞增生和疼痛传感器表达。吗啡给药可以更快地增加烧伤部位的伤害性,并加重脊髓小胶质细胞增生和炎性疼痛传感器的表达。GTS-21具有治疗烧伤中吗啡引起的疼痛的潜力。
Repetitive opioid use does not always alleviate basal pain, procedural pain, or both after burn injury. Mitigation of burn injury-site pain can be achieved by GTS-21 stimulation of α7-acetylcholine nicotinic receptors (α7AChRs) and reduced microglia activation in rat. We tested the hypothesis that morphine exaggerates burn injury-site pain and GTS-21 alleviates both morphine-induced aggravated burn injury pain and microglia activation.
Young rats with dorsal paw burn injury or sham-burn received intraperitoneal saline, morphine, GTS-21, or a combination twice daily for 14 days. Ipsilateral plantar pain thresholds were tested every other day before morning drugs from days 0-20. Spinal microglia activation, evidenced as pain-transducer (tumour necrosis factor-α [TNF-α], interleukin [IL]-6, IL-1β, nuclear factor kappa B [NF-κB], Toll-like receptor 4 [TLR4]) expression, was examined using immunohistochemistry and immunoblot. In cultured microglia, morphine-induced cytokine expression was measured (quantitative polymerase chain reaction/enzyme-linked immunosorbent assay [qPCR/ELISA]).
Morphine aggravated allodynia at day 5 in sham-burn (P=0.039, n=8-11) but significantly aggravated burn injury site allodynia by day 3 (P=0.010, n=8-11). Microgliosis paralleled nociceptive behaviour changes where burn injury with morphine had highest microgliosis compared with burn injury, morphine alone, or controls (number of cells per field [SD]: 33.8 [2.4], 18.0 [4.1], 8.2 [1.9], and 4.8 [2.0], respectively; P<0.001, n=4-5]. GTS-21 reversed the morphine-induced pain component in sham-burn and burn injury rats together with reduced microgliosis and spinal pain-transducer expression (TNF-α, IL-6, IL-1β, NF-κB, and TLR4). Morphine-exposed microglial cells showed increased cytokine expression, which was mitigated by GTS-21.
Morphine or burn injury alone increases pain together with microgliosis and pain-transducer expression. Morphine administration augments burn injury-site nociception sooner and aggravated spinal microgliosis and inflammatory pain-transducer expression. GTS-21 has the potential to treat morphine-induced pain in burn injury.